Tablet formulation

ABSTRACT

The disclosure is directed to formulations for tablets which are to be deeply grooved to facilitate breaking into predetermined portions by the user. A critical tablet weight for deeply grooved tablets is disclosed.

United States Patent 1 Geller [4 1 May 13, 1975 TABLET FORMULATION [75]Inventor: Ehud Geller, King of Prussia, Pa.

[73] Assignee: Ives Laboratories, New York, N.Y.

[22] Filed: Dec. 6, 1972 [21] Appl. No.: 312,469

[52] US. Cl. 424/15; 424/362, 424/6 [51] Int. Cl A61] 3/10; A6lk 9/00[58] Field of Search 424/15, 6, 362

[56] References Cited UNITED STATES PATENTS 1,836,604 12/1931 Meyer127/30 3,146,168 8/1964 Battista 424/362 3,336,200 8/1967 Krause eta1... 424/19 3,723,614 3/1973 Langauer 424/15 D9l,644 3/1934 BlackstoneD16/3 D201,497 6/1965 Ninger D1613 D202,467 10/1965 Guilmot D1613FOREIGN PATENTS OR APPLICATIONS 1,200,790 9/1965 Germany 352,208 9/1937Italy 6,614,61 l 4/1967 Netherlands OTHER PUBLICATIONS Reier et al., J.Pharm. Sci. 55(5), 510-514, (1966), Microcrystalline Cellulose inTableting." Reier, Dissertation Abtr. 25(5), 2933 (1964),Microcrystalline Cellulose in Tableting." Fox et al., Cosmetic Ind. 92,161-164, 258-261, (1963), Microcrystalline Cellulose in Tabletting."Battista et al., Ind. Eng. Chem. 54(9), 20-29, (1962), MicrocrystallineCellulose. Woods, Am. Perfumer Cosmet. 80(4), 51-53, 55-60, (1965),Microcrystalline Cellulose, A New Ingrediem for Pharmaceuticals andCosmetics."

Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Joseph MartinWeigman {57] ABSTRACT The disclosure is directed to formulations fortablets which are to be deeply grooved to facilitate breaking intopredetermined portions by the user. A critical tablet weight for deeplygrooved tablets is disclosed.

5 Claims, 6 Drawing Figures TABLET FORMULATION This invention relates tonovel formulations for tablets which are to be deeply grooved. Deeplygrooved tablets are those in which the groove is one-third to two-thirdsof the total tablet thickness. Such tablets are shown for instance inU.S. Pat. No. 224,591 and in copending applications Ser. No. 386,l42filed Aug. 6, I973 which is a continuation-in-part of Ser. No. 312,065filed Dec. 4, I972 and now abandoned which was in turn a combination ofSer. No. ll4,926 filed Feb. 12, 1971 and Ser. No. 124,894 filed Mar. 16,I971. The foregoing patent and applications were all filed by Edwin F.Roberts and assigned to the assignee of this application. The tabletdesign allows for easy, simple and accurate division of a pharmaceuticaltablet.

in the manufacture of tablets a groove, or bisect, or score, may beformed on one of the tablet faces. The groove facilitates breaking ofthe tablet into two parts by applying pressure while the tablet is heldbetween two fingers or in both hands.

In the pharmaceutical industry dividing a tablet into two or moreaccurate predetermined parts permits the administration of two or moredoses of the active ingredient, or drug, contained in the tablet. Potentdrugs are frequently incorporated in small amounts into a total tabletformulation, and the capability to divide the tablet accurately allowsfor a saving by not having to formulate, package and distributedifferent sized tablets for a portion of the dose and for the full dose.In addition, it is often beneficial to the chemical stability of thedrug to incorporate the full dose in the smallest tablet size available.The inclusion of one-half of that dose in a tablet of similar sizedecreases the relation of drug to excipients twofold, thus in many casesalso increasing the possibility of drug degradation due to drugexcipientinteraction.

Some of the problems that arise in the production of regularly groovedtablets are:

l. Depending on its hardness, it is sometimes impossible to break thetablet although it is scored.

2. Scores do not always assure precise division of the tablet.

3. Pharmaceutical tablets of smaller sizes do not allow for ease ofholding and breaking; in which case the patient very often resorts tousing other means of dividing the tablet which results in losing partsof it or obtaining uneven parts or both.

Typical deeply scored tablets to which the present invention isapplicable are shown in the drawings in which:

FIG. 1 is an isometric view ofa pharmaceutical tablet employing a deeplyscored design;

FIG. 2 is a top plan view thereof;

FIG. 3 is a side elevational view thereof as seen at right angles toFIG. 2;

FIG. 4 is an end elevational view thereof as seen at right angles toFIG. 2;

FIG. 5 is an end elevational view ofa pharmaceutical tablet embodying amodification of the form illustrated in FIG. 4; and

FIG. 6 is a bottom view of the embodiments of FIGS. 1 and 5.

The deeply grooved tablet design presents tablet compressioncharacteristics which are not typical of the manufacturing ofconventional pharmaceutical tab lets. While tablets are usuallycompacted between uniform surfaces, flat or concave, the deeply groovedtablet design presents a non-uniform compressing surface on one tabletface and a uniform face, spherical or flat, on the other. Such amultiplanar surface presents a process of physical compaction which doesnot produce the results expected from a conventional compressed tablet.In the process of compaction, the multiplanar surface applies forces,the resultant of which is not vertical. This results in non-uniformstress distribution within the tablet as an independent unit which inturn causes tablet capping and the inadequate imprinting or embossing ofindicia of any of its surfaces. In addition, the uneven distribution ofstresses results in varying levels oflubrication effectiveness of thetablet planes in contact with the press tooling which, in turn, causespicking" of material off the tablet surface. To overcome this phenomenonrequires a highly cohesive mixture which is at the same timesufficiently lubricated to enable friction-free tooling to tabletcontact on all tablet planes. In practice the tablet formulator has tobalance the lubricant level against the binder level because theincrease of the former will diminish the effect of the latter until thecritical region of such action is surpassed.

Picking" and sticking are words of art, meaning part of the tabletsticks to the tips of the upper or lower punch. Capping describes acondition in which the tablet laminates into one or more layers.

This invention has been directed principally to the application ofspecific pharmaceutical formulations incorporating isosorbide dinitrateas the active ingredient, but is applicable to other deeply groovedtablets as well. lsosorbide dinitrate is a potent coronary vasodilator.

It was originally presumed that existing, acceptable, directcompression, tableting compositions could be adequately compressed withdeep scoring tooling. Two such compositions were evaluated andsurprisingly, it was found that acceptable tablets could not be made.Using a placebo composition (one without an active ingredient) similarto a presently used acceptable isosorbide dinitrate tablet composition,it was determined that, unexpectedly, a total tablet weight was criticalto obtain acceptable tablets. To minimize the problems caused by stressnon-uniformity, an optimal weight was found where after sufficientcompression the distance between the apex of the convex side of thetablet and the bottom of the V-shaped opening on top will be minimalwhile still allowing for adequate manufacturability.

Having established the critical tablet weight, it was expected thatcompositions containing the active ingredient would tablet in anacceptable manner because acceptable tablets could be made at thiscomposition using conventional tools. However, unexpectedly, it wasfound that a critical binder-lubricant relationship was needed toproduce acceptable tablets with deep scoring tooling.

Four experiments were designed to select the most optimal tablet weightfor the easy-break design. The data is shown in Example I.

EXAMPLE 1 TOTAL TABLET WEIGHT OPTIMIZATION All experiments were run induplicates from one stock powder mixture and directly compressed on arotary tablet press. The material run was an optimal placebo mixture 88des ri d below? order to resolve the problem a set of experiments wasFORMLFLAE. A B C D Lactose hydrous U.S.P. qs qs qs qs MicrocrystallineCellulose 25 W 25 Wk) 25 w/o 25 w/o Magnesium Stcarate USP. 0.25 w/o0.25 w/o 0.25 w/o 0.25 w/o Total Tablet Weight 230 mg 200 mg 175 mg l50mg designed to determine the critical nature of the binder and lubricantlevels. The experiments are shown in Example ll:

EXAMPLE ll Following the procedure of Example I a series of formulationswere prepared and deeply scored tablets were made from them. Theformulations are shown in Table l.

TABLE I PERCENT OF TOTAL TABLET WEIGHT FORMULA A B C D E F g H l J KMicrocrystalline Cellulose 25 25 25 45 45 25 25 25 60 'Solkafloc l0Lactose. hydrous s qs qs qs qs qs qs qs qs qs Lactose. anhydrous 63Dicalcium Phosphate Sta-Rx I500 74 Magnesium Stcaratc 0.22 0.3 0.22 0.220.3 0.22 0.35 0.3 0.3 0.4 0.35 Stcaric Acid "Stcro-Tex 0.50 Tale 2lsosorbide Dinitrate Trituration 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.020.0 20.0 200 mg mg mg mg mg mg mg mg mg mg mg Total Weight mg 175 I75175 175 175 175 175 I75 I75 175 175 Formulas A through H with theexception of G did not exhibit adequate manufacturahility in a directioncompression process.

I) Purified Cellulose, Brown Co. 1 Directly compressible starch 1"!Edible vegetable oil. powdered iubricunl FORMULA C: Producedsatisfactory tablet hardness of 8-l4 s.c.u. and friability of 0.0% atthat range. FORMULA D: Produced satisfactory tablets.

Initially it was tried to utilize a conventional isosorbide dinitrateformula and weight for the easy-break tableting tools. It was expectedthat the design would perform adequately at a total weight of 230milligrams (mg). Surprisingly the tablets made at this weight wereunsatisfactory. and evidenced capping, high friability in addition toinsufficient tablet hardness. An attempt was made to solve the problemby selecting the most adequate tablet weight to achieve bettermanufacturability, but was unsuccessful The weight selection experimentsindicated that in order to achieve adequate tableting parameters withdeep scoring tooling the tablet weight will have to be under 200 mg. Theoptimum weight is about 175 mg because at 150 mg there is a highprobability of tooling contact which in turn may cause damage to thepunch tips.

Once the weight problem was solved. no further problems wereanticipated. However, upon careful scrutiny of the tableting performancethere was found an unexpected problem in the binder and lubricantrelationship. "Picking" and *sticking" were found in some cases and softtablets with capping in others. in

FORMULA B contained the minimal level of anhydrous lactose to produce anadequate tablet. However, the tablet demonstrated poor disintegration.

FORMULA C produced soft tablets that capped while still picking.

FORMULA D exhibited insufficient hardness range and picking on bothtablet faces.

FORMULA E showed insufficient binding resulting in very soft tabletshaving high friabilityl FORMULA F showed inadequate performance becauseof slight pick.

FORMULA G showed adequate manufacturability as to hardness andfriability. The tablets were free of pick ing.

FORMULA H showed insufficient hardness with picking on bottom face.

cause the design of a chewable tablet requires the incorporation of achewable carrier, it was necessary to evaluate different chewablematerials to obtain a sufficiently cohesive and well lubricated directcompression formula. The data obtained in those experiments is 5 FORMULA1 was a siugged f m which cxhibied shown in Table 11 m which the tabletswere prepared as binding and picking on the tablet lower face. describedin Example 1.

TABLE 11 CHEWABLE TABLETS FORMLFLAE A B C D E F G H lsosorbide Dinitratc(25%] 40 mg 40 mg 40 mg 40.0 mg 40 mg 40 mg 40.0 mg 40.0 mg Lactosemixture *Nutah qs qs Mannitol U.S.P. qs 20% 20% qs *Cellutab. anhydrous31.5% 31.5% 31.5% qs Microcrystalline Cellulose 25.0% 20% 25% 25% 25%20)? Solka floc 810% Magnesium Stearate use 0.6% 0.7% 1.0% 1.0% 0.5%0.9% 0.-J%+0.9% 0.35% FD&C Yellow No. 5 Lake 01')? 0.1% 0.4% 0.4% 0.4%0.4% 0.4% 0.4% Sodium Saccharine NF. 0.08% 0.08% 0.08% 0.08% MethylCellulose 400 cps 07% Lemon Oil. spray dried 1.7% 1.7% 1.7% 1.7% 1.7%

1.7% Total Tablet Weight 222.5 196 190 175.0 175 175 175.0 175 mg mg mgmg mg mg mg mg Sucrose. invert sugar, starch. magnesium stearate directcompression granulation.

"Dextrose and corn syrup solids granulation FORMULA J was a sluggedformula with a higher lubricant level which produced adequatelubrication but insufficient hardness.

FORMULA K showed excellent manufacturability for all parameters.

Based on the foregoing it was determined that tablets made ofconventional pharmaceutical ingredients would manufacture adequately atweights under 200 mg. utilizing a deeply scored design. In addition, agreat amount of experimentation and design was spent on the tabletformulation to overcome the critical nature of its binder and lubricantdependence From the foregoing the preferred weight for deeply groovedtablets is 150 to 175 mg. The preferred ratio of lubricant to binder isobtained when the binder constitutes 45 to 99.7 w/o and the lubricantconstitutes 0.3 to 0.4 w/o of tablet exclusive of the amount of theactive ingredient, fillers, extenders. flavor and the like. That is, theweight per cent of the binder and lubricant is based on the portion ofthe tablet composition usually referred to as q.s.

Only microcrystalline cellulose of the binders presently available onthe market has been found to be use ful in deep grooved tabletcompositions. Only the stearates. including stearic acid, of thelubricants presently available on the market have been found to beuseful in deep grooved tablet compositions.

A particularly advantageous formula weighs 175 mg. per tablet andcontains 60 percent by weight microcrystalline cellulose with 0135percent by weight of magnesium stearate.

For assuring of distintegration and dissolution reproducibility the useof 1 percent Amberlite is optional and has been tested to that effect.

EXAMPLE lll Preparation of 10 mg. lsosorbide Dinitrate Chewable TabletsThe deeply scored design was also utilized in the manufacture of achewable tablet form containing iso sorbide dinitrate at a 10 mg. level.

Again, in this formula it was found necessary to resort to a lowertablet weight of 175 mg. ln addition. be-

Formulae A, B, D. E and F are directly compressed.

Formula A exhibited very high friability. capping and a narrow hardnessrange.

In Formula B the weight has been reduced, but tablets still exhibitheavy capping and friability with very low hardness.

Formula C was a wet granulated formula, and exhibited high friability,capping and inadequate chewability due to the wet binder.

Formula D shows adequate manufacturability and chewability.

in Formula E reduced lubricant level results in heavy picking on bothtablet faces.

1n Formula F eliminating the sweetener from For mula D maintainsadequate manufacturability with improved taste.

Formula G was slugged and exhibited capping, narrow hardness range andslight picking.

Formula H produced adequate tableting characteristics.

From the foregoing it was concluded that 10 mg. chewable tablets weresuccessfully made in two formulations:

l. The first formulation uses a directly compressed mannitol and adextrose and corn syrup solids granulation in combination;

2. The second formulation uses dextrose and corn syrup solidsgranulation without mannitol in direct compression.

The choice between these two categories depends strictly on personaltaste preference. Both formulae will produce similarly adequate results.

The preferred embodiment at which chewable deeply scored tablets can bemade is for the first category with at least 20 percent by weight ofmicrocrystallinc cellulose, 31.5 percent by weight of Cellutabanhydrous. 25 percent mannitol and a range of 0.7-1.0 percent by weightof magnesium stearate Jr: at the second category with Cellutab anhydrousand a minimum of 0.35 percent by weight of magnesium stearatc.

The incorporation of an ingredient which would serve as a chewablecarrier, one which imparts a cer tain pallatable feeling, sweetness anddesirable chewability, presents additional variables to the ones alreadydescribed above. When processing and formulating for such purpose. it isnecessary to consider the properties producing the resulting chewablequality of the tablet. that is hardness, taste and pallatability. Themajority of chewable carriers, apart from the granulated natural sugarsand their derivatives, do not lend themselves to direct compression andtend to lose some of their taste upon any granulation method.

The examples illustrated in Table II present the compositions ofpharmaceutical tablets manufactured by three basic methods: directcompression. dry granulation, and wet granulation. These examples arenot to be construed as limiting the scope of this invention which mayonly be determined by reference to the appended claims.

What is claimed is:

l. A pharmaceutical tablet which is adequately imprinted with indicia orembossing and scored to form a groove which is one-third to two-thirdsthe depth of the total tablet thickness to facilitate separation intosubdivisions containing substantially equal amounts of apharmaceutically active ingredient comprising a directly compressedformulation of 5 to 10 milligrams of an active ingredient, the remainderbeing 45 to 99.7 percent by weight of microcrystalline cellulose and 0.3to 0.4 percent by weight of magnesium stearate, along with fillers.extenders, flavoring and the like.

2. The tablet as defined in claim 1 in which the total tablet weight is[50 to 175 milligrams.

3. A tablet as defined in claim 1 in which the total tablet weight isabout l milligrams 4. A tablet as defined in claim 1 in which themicrocrystalline cellulose is present in the amount of 60 percent byweight and the magnesium stearate is present in the amount of 0.35percent by weight.

5. A tablet as defined in claim 1 in which the active ingredient is S to10 milligrams of isosorbide dinitratev i

1. A PHARMACEUTICAL TABLET WHICH IS ADEQUATELY IMPRINTED WITH INDICIA OREMBOSING AND SCORED TO FORM A GROOVE WHICH IS ONE-THIRD TO TWO-THIRDSTHE DEPTH OF THE TOTAL TABLET THICKNES TO FACTILITATE SEPARATION INTOSUBDIVISIONS CONTAINING SUBSTANTIALLY EQUAL AMOUNTS OF APHARMACEUTICALLY ACTIVE INGREDIENT COMPRISING A DIRECTLY COMPRESSEDFORMULATION OF 5 TO 10 MILLIGRAMS OF AN ACTIVE INGREDIENT, THE REMAINDERBEING 45 TO 99.7 PERCENT BY WEIGHT OF MICROCRYSTALLINE CELLULOSE AND 0.3TO 0.4 PERCENT BY WEIGHT OF MAGNESIUM STEARATE, ALONG WITH FILLERS,EXTENDERS, FLAVORING AND THE LIKE.
 2. The tablet as defined in claim 1in which the total tablet weight is 150 to 175 milligrams.
 3. A tabletas defined in claim 1 in which the total tablet weight is about 175milligrams.
 4. A tablet as defined in claim 1 in which themicrocrystalline cellulose is present in the amount of 60 percent byweight and the magnesium stearate is present in the amount of 0.35percent by weight.
 5. A tablet as defined in claim 1 in which the activeingredient is 5 to 10 milligrams of isosorbide dinitrate.